rs3802805

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_021926.4(ALX4):c.1074C>T(p.His358His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,612,836 control chromosomes in the GnomAD database, including 101,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8218 hom., cov: 33)

Exomes 𝑓: 0.35 ( 93155 hom. )

Consequence

ALX4
NM_021926.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.55

Variant links:

Genes affected

ALX4 (HGNC:450): (ALX homeobox 4) This gene encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones, limbs, hair, teeth, and mammary tissue. Mutations in this gene cause parietal foramina 2 (PFM2); an autosomal dominant disease characterized by deficient ossification of the parietal bones. Mutations in this gene also cause a form of frontonasal dysplasia with alopecia and hypogonadism; suggesting a role for this gene in craniofacial development, mesenchymal-epithelial communication, and hair follicle development. Deletion of a segment of chromosome 11 containing this gene, del(11)(p11p12), causes Potocki-Shaffer syndrome (PSS); a syndrome characterized by craniofacial anomalies, cognitive disability, multiple exostoses, and genital abnormalities in males. In mouse, this gene has been shown to use dual translation initiation sites located 16 codons apart. [provided by RefSeq, Oct 2009]

ALX4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 11-44265016-G-A is Benign according to our data. Variant chr11-44265016-G-A is described in ClinVar as [Benign]. Clinvar id is 304701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44265016-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALX4	NM_021926.4 link	c.1074C>T	p.His358His	synonymous_variant	Exon 4 of 4	ENST00000652299.1	NP_068745.2	Q9H161

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1 link	c.1074C>T	p.His358His	synonymous_variant	Exon 4 of 4		NM_021926.4	ENSP00000498217.1		Q9H161

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46686

AN:

152044

Hom.:

8203

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.359

Gnomad AMR

AF:

0.453

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.347

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.333

Gnomad OTH

AF:

0.336

GnomAD3 exomes

AF:

0.373

AC:

93097

AN:

249426

Hom.:

19228

AF XY:

0.369

AC XY:

49992

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.548

Gnomad SAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.350

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

AF:

0.350

AC:

511825

AN:

1460674

Hom.:

93155

Cov.:

AF XY:

0.351

AC XY:

254850

AN XY:

726672

show subpopulations

Gnomad4 AFR exome

AF:

0.153

Gnomad4 AMR exome

AF:

0.558

Gnomad4 ASJ exome

AF:

0.229

Gnomad4 EAS exome

AF:

0.521

Gnomad4 SAS exome

AF:

0.393

Gnomad4 FIN exome

AF:

0.343

Gnomad4 NFE exome

AF:

0.342

Gnomad4 OTH exome

AF:

0.348

GnomAD4 genome

AF:

0.307

AC:

46736

AN:

152162

Hom.:

8218

Cov.:

AF XY:

0.313

AC XY:

23267

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.166

Gnomad4 AMR

AF:

0.453

Gnomad4 ASJ

AF:

0.246

Gnomad4 EAS

AF:

0.534

Gnomad4 SAS

AF:

0.386

Gnomad4 FIN

AF:

0.347

Gnomad4 NFE

AF:

0.333

Gnomad4 OTH

AF:

0.341

Alfa

AF:

0.324

Hom.:

9792

Bravo

AF:

0.312

Asia WGS

AF:

0.477

AC:

1655

AN:

3478

EpiCase

AF:

0.329

EpiControl

AF:

0.326

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Parietal foramina 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontonasal dysplasia with alopecia and genital anomaly

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.1

DANN

Uncertain

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over